TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment
Grazia Scandura,
Cesarina Giallongo,
Fabrizio Puglisi,
Alessandra Romano,
Nunziatina Laura Parrinello,
Tatiana Zuppelli,
Lucia Longhitano,
Sebastiano Giallongo,
Michelino Di Rosa,
Giuseppe Musumeci,
Roberto Motterlini,
Roberta Foresti,
Giuseppe Alberto Palumbo,
Giovanni Li Volti,
Francesco Di Raimondo,
Daniele Tibullo
Affiliations
Grazia Scandura
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Cesarina Giallongo
Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Fabrizio Puglisi
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Alessandra Romano
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Nunziatina Laura Parrinello
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Tatiana Zuppelli
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Lucia Longhitano
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Sebastiano Giallongo
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Michelino Di Rosa
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Giuseppe Musumeci
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Roberto Motterlini
Faculty of Health, University Paris-Est Créteil, INSERM, IMRB, 94010 Créteil, France
Roberta Foresti
Faculty of Health, University Paris-Est Créteil, INSERM, IMRB, 94010 Créteil, France
Giuseppe Alberto Palumbo
Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Giovanni Li Volti
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Francesco Di Raimondo
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Daniele Tibullo
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Relapse in multiple myeloma (MM) decreases therapy efficiency through unclear mechanisms of chemoresistance. Since our group previously demonstrated that heme oxygenase-1 (HO-1) and Toll-like receptor 4 (TLR4) are two signaling pathways protecting MM cells from the proteasome inhibitor bortezomib (BTZ), we here evaluated their cross-regulation by a pharmacological approach. We found that cell toxicity and mitochondrial depolarization by BTZ were increased upon inhibition of HO-1 and TLR4 by using tin protoporphyrin IX (SnPP) and TAK-242, respectively. Furthermore, the combination of TAK-242 and BTZ activated mitophagy and decreased the unfolded protein response (UPR) survival pathway in association with a downregulation in HO-1 expression. Notably, BTZ in combination with SnPP induced effects mirroring the treatment with TAK-242/BTZ, resulting in a blockade of TLR4 upregulation. Interestingly, treatment of cells with either hemin, an HO-1 inducer, or supplementation with carbon monoxide (CO), a by-product of HO-1 enzymatic activity, increased TLR4 expression. In conclusion, we showed that treatment of MM cells with BTZ triggers the TLR4/HO-1/CO axis, serving as a stress-responsive signal that leads to increased cell survival while protecting mitochondria against BTZ and ultimately promoting drug resistance.
